Abstract
The discovery of chemical reactions is an inherently unpredictable and time-consuming process1. An attractive alternative is to predict reactivity, although relevant approaches, such as computer-aided reaction design, are still in their infancy2. Reaction prediction based on high-level quantum chemical methods is complex3, even for simple molecules. Although machine learning is powerful for data analysis4,5, its applications in chemistry are still being developed6. Inspired by strategies based on chemists’ intuition7, we propose that a reaction system controlled by a machine learning algorithm may be able to explore the space of chemical reactions quickly, especially if trained by an expert8. Here we present an organic synthesis robot that can perform chemical reactions and analysis faster than they can be performed manually, as well as predict the reactivity of possible reagent combinations after conducting a small number of experiments, thus effectively navigating chemical reaction space. By using machine learning for decision making, enabled by binary encoding of the chemical inputs, the reactions can be assessed in real time using nuclear magnetic resonance and infrared spectroscopy. The machine learning system was able to predict the reactivity of about 1,000 reaction combinations with accuracy greater than 80 per cent after considering the outcomes of slightly over 10 per cent of the dataset. This approach was also used to calculate the reactivity of published datasets. Further, by using real-time data from our robot, these predictions were followed up manually by a chemist, leading to the discovery of four reactions.
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Change history
26 June 2019
Change history: Owing to the misidentification of compound 22 in the original Letter, changes have been made to Fig. 5, Extended Data Fig. 2 and the main text; see accompanying Amendment.
24 July 2018
The chemical structure formatting in Fig. 5 has been corrected online.
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Acknowledgements
We acknowledge financial support from the EPSRC (grants number EP/H024107/1, EP/I033459/1, EP/J00135X/1, EP/J015156/1, EP/K021966/1, EP/K023004/1, EP/K038885/1, EP/L015668/1 and EP/L023652/1) and the ERC (project 670467 SMART-POM). J.M.G. acknowledges financial support from the Polish Ministry of Science and Higher Education grant number 1295/MOB/IV/2015/0. We thank A. Henson for help with the Tanimoto analysis.
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Contributions
L.C. conceived the idea, developed the initial algorithms, designed the project and coordinated the efforts of the research team. J.M.G. developed the machine learning algorithms and devised the LDA and built and programmed the chemical robot. J.M.G. conducted experiments and isolated and characterized new compounds with input from L.D. and V.D. J.M.G. and L.C. co-wrote the paper with input from all authors.
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L.C. is the founder and director of DeepMatterGroup PLC and is listed as an inventor on a patent application filed by The University of Glasgow (GB 1810944.7).
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Extended data figures and tables
Extended Data Fig. 1 Reaction space explored.
The chemical inputs (1–18) used in the platform to search for new transformations and to evaluate the performance of the algorithm.
Extended Data Fig. 2 Suggested mechanisms for observed transformations and small library of compounds synthesized.
a, Suggested mechanism for the synthesis of compound 19. b, Small library of compounds synthesized. c, Suggested mechanism for the synthesis of compound 22. d, Suggested mechanism for the synthesis of compound 21.
Supplementary information
Supplementary Information
This file contains Supplementary Tables 1–6, Supplementary Figures 1–73, hardware specification, machine learning details, characterization of new compounds, structural assignments and copies of NMR spectra.
Supplementary Data
This zipped file contains the X-ray structure of compound 20.
Supplementary Data
This zipped file contains the X-ray structure of compound 21.
Supplementary Table
This table shows exemplary run of LDA algorithm exploring the chemical space. The first ninety experiments were chosen randomly and the next subsequent experiments were chosen using the LDA classifier. The name column contains the identity of the reaction composed from the names of the starting materials. The reactivity column contains the assignment of reactivity from SVM classifier for a given reaction mixture.
Supplementary Table
This table contains the LDA scores for all 969 reaction formed from chemical space shown in Extended Data Fig. 1. The LDA_reactivity column contains scores from LDA and reactivity column contains the assignment of reactivity from SVM classifier for a given reaction mixture.
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Granda, J.M., Donina, L., Dragone, V. et al. Controlling an organic synthesis robot with machine learning to search for new reactivity. Nature 559, 377–381 (2018). https://doi.org/10.1038/s41586-018-0307-8
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DOI: https://doi.org/10.1038/s41586-018-0307-8
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